One of the major goals of organic chemical research has always been the synthesis of antimicrobial compounds. Such compounds have been and continue to be in demand for use as human and veterinary medicines, as disinfectants for hospitals, floors and the like, and as agents for control of plant diseases. There is a continuing demand for antimicrobials cheaper and safer than those in use, as well as compounds for the control of organisms which have grown resistant to the compounds now in use.
A number of useful antimicrobials have come from the general field of hetero-ring compounds. The nitrofurans, for example, have yielded several valuable compounds. Many other ring systems have not been extensively explored as a source of antimicrobials. The 3-nitropyrazoles, for example, have appeared only occasionally in the chemical literature, and have not previously been known as microbiocides.
Habraken et al., Tetrahedron Letters 7, 479 (1970), disclosed the preparation of 1-methyl-3-nitro-4-pyrazolecarboxylic acid by nitration of a 1,4-dimethylpyrazole with acetyl nitrate, followed by oxidation of the 4-methyl substituent.
Parham and Aldre, J. Org. Chem. 25, 1259 (1960), prepared as 3(5)-nitropyrazole by replacement of the amine group in 3(5)-amino-4-phenylpyrazole through an intermediate diazonium salt. The amino compound was dissolved in fluoboric acid solution, chilled in an ice-salt bath, and stirred while a cold solution of sodium nitrite was added very slowly. The diazonium fluoborate precipitated, was filtered off and washed, and was then converted into 3(5)-nitro-4-phenylpyrazole by reaction with sodium nitrite in the presence of metallic copper.
A preparation of 3-nitro-1-phenylpyrazole was taught by Coburn, J. Heterocyclic Chem. 7, 455 (1970). The process was an oxidation of 3-amino-1-phenylpyrazole with an excess of anhydrous peroxytrifluoroacetic acid. No utility of the product was disclosed, and the process was not extended to other 3-nitropyrazoles.
Another preparation of a 3-nitropyrazole was described by Parham and Bleasdale, J. Am. Chem. Soc. 73, 4664 (1951). They made 3(5)-nitro-4-phenylpyrazole from 3-bromo-3-nitro-4-phenylpyrazoline by decomposition with sodium bicarbonate. Their purified product was recovered by chromatography.
Wolf and Flanigan, U.S. Pat. No. 3,303,200, taught the preparation of 1-(2-hydroxyalkyl)pyrazoles. They disclosed that any of some 14 groups, including nitro, could be substituted at the 3-, 4-, or 5-positions on the pyrazole ring, but they taught no preparative methods or utility of 3-nitropyrazoles.
None of the above references taught antimicrobial, parasiticidal, or herbicidal properties for the compounds which they disclosed.
Cheng, J. Heterocyclic Chem. 5, 195 (1968), described a preparation of 1-methyl-5-nitro-4-pyrazolecarboxylic acid, which is isomeric with our 1-methyl-3-nitro-4-pyrazolecarboxylic acid. Derivatives of the 5-nitro acid, however, do not exhibit biological activity comparable to that of the corresponding 3-nitro derivatives.
Antimicrobial compounds somewhat related to the 3-nitropyrazoles are known. For example, Hoff, U.S. Pat. No. 3,715,364, disclosed an interesting series of antiparasitic 5-nitroimidazoles. A 4-nitro-5-pyrazolecarbonitrile, said to be useful as a coccidiostat, was disclosed by Geiszler, U.S. Pat. No. 3,121,092.
Interesting 5-nitroimidazoles, useful for the control of blackhead disease, were disclosed by Asato et al., U.S. Pat. No. 3,565,892, by Vatre et al., U.S. Pat. No. 3,439,097, and by Henry, U.S. Pat. No. 3,378,552.